Although most patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) initially respond to therapy including prednisone or other glucocorticoids, the disease often becomes steroid-resistant at relapse. Our primary objective is to contribute to an understanding of the molecular mechanisms of steroid resistance. Research specimens will include peripheral blood, bone marrow, and lymph nodes of pediatric patients with ALL or NHL, at diagnosis, in remission, or at relapse, and normal peripheral blood. Specific studies will include: 1) purification of lymphocytes and lymphoblasts by multi-step density gradient centrifugation and/or by agglutination with peanut lectin or differential binding of fluorescent-labeled lectin and use of the fluorescence activated cell-sorter; 2) characterization of the resultant preparations with respect to surface immunoglobulins, rosette formation with sheep red blood cells, terminal deoxynucleotidyl transferase, and whole-cell binding of (3H)glucocorticoids; 3) stabilization of glucocorticoid receptors in extracts of cells and nuclei, and characterization by ultracentrifugal, chromatographic and electrophoretic techniques; 4) comparisons of the ability of lymphocytes or lymphoblasts from steroid-responsive and -resistant patients to metabolize the hormones used in therapy (dexamethasone, prednisone) or their hepatic metabolites (e.g., prednisolone); and 5) fluorometric assays of secreted proteolytic enzymes that may function as lymphocyte stimulatory factors. Laboratory results will be correlated with each other and with well-defined parameters of clinical response by rigorous statistical methods. Eventual applications of these findings may include: 1) new, highly sensitive methods to predict and monitor the therapeutic effectiveness of steroids in individual patients; 2) new glucocorticoid analogs with more favorable pharmacokinetics; and 3) new therapeutic approaches, e.g., inhibitors of the putative lymphocyte stimulatory factors.